Gentulizumab, a novel anti-CD47 antibody with potent antitumor activity and demonstrates a favorable safety profile
Abstract Background Targeting CD47/SIRPα axis has emerged as a promising strategy in cancer immunotherapy. Despite the encouraging clinical efficacy observed in hematologic malignancies through CD47-SIRPα blockade, there are safety concerns related to the binding of anti-CD47 antibodies to CD47 on t...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-03-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-023-04710-6 |
| _version_ | 1797273479519666176 |
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| author | Tao Wang Si-Qin Wang Yin-Xiao Du Dan-Dan Sun Chang Liu Shuang Liu Ying-Ying Sun Hai-Long Wang Chun-Sheng Zhang Hai-Long Liu Lei Jin Xiao-Ping Chen |
| author_facet | Tao Wang Si-Qin Wang Yin-Xiao Du Dan-Dan Sun Chang Liu Shuang Liu Ying-Ying Sun Hai-Long Wang Chun-Sheng Zhang Hai-Long Liu Lei Jin Xiao-Ping Chen |
| author_sort | Tao Wang |
| collection | DOAJ |
| description | Abstract Background Targeting CD47/SIRPα axis has emerged as a promising strategy in cancer immunotherapy. Despite the encouraging clinical efficacy observed in hematologic malignancies through CD47-SIRPα blockade, there are safety concerns related to the binding of anti-CD47 antibodies to CD47 on the membrane of peripheral blood cells. Methods In order to enhance the selectivity and therapeutic efficacy of the antibody, we developed a humanized anti-CD47 monoclonal antibody called Gentulizumab (GenSci059). The binding capacity of GenSci059 to CD47 was evaluated using flow cytometry and surface plasmon resonance (SPR) methods, the inhibitory effect of GenSci059 on the CD47-SIRPα interaction was evaluated through competitive ELISA assays. The anti-tumor activity of GenSci059 was assessed using in vitro macrophage models and in vivo patient-derived xenograft (PDX) models. To evaluate the safety profile of GenSci059, binding assays were conducted using blood cells. Additionally, we investigated the underlying mechanisms contributing to the weaker binding of GenSci059 to erythrocytes. Finally, toxicity studies were performed in non-human primates to assess the potential risks associated with GenSci059. Results GenSci059 displayed strong binding to CD47 in both human and monkey, and effectively inhibited the CD47-SIRPα interaction. With doses ranging from 5 to 20 mg/kg, GenSci059 demonstrated potent inhibition of the growth of subcutaneous tumor with the inhibition rates ranged from 30.3% to complete regression. Combination of GenSci059 with 2.5 mg/kg Rituximab at a dose of 2.5 mg/kg showed enhanced tumor inhibition compared to monotherapy, exhibiting synergistic effects. GenSci059 exhibited minimal binding to hRBCs compared to Hu5F9-G4. The binding of GenSci059 to CD47 depended on the cyclization of N-terminal pyroglutamic acid and the spatial conformation of CD47, but was not affected by its glycosylation modifications. A maximum tolerated dose (MTD) of 450 mg/kg was observed for GenSci059, and no significant adverse effects were observed in repeated dosages up to 10 + 300 mg/kg, indicating a favorable safety profile. Conclusion GenSci059 selectively binds to CD47, effectively blocks the CD47/SIRPα axis signaling pathway and enhances the phagocytosis effects of macrophages toward tumor cells. This monoclonal antibody demonstrates potent antitumor activity and exhibits a favorable safety profile, positioning it as a promising and effective therapeutic option for cancer. |
| first_indexed | 2024-03-07T14:43:54Z |
| format | Article |
| id | doaj.art-a1c03c450dda44e1a36c6d58ab761d99 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-03-07T14:43:54Z |
| publishDate | 2024-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-a1c03c450dda44e1a36c6d58ab761d992024-03-05T20:07:28ZengBMCJournal of Translational Medicine1479-58762024-03-0122111310.1186/s12967-023-04710-6Gentulizumab, a novel anti-CD47 antibody with potent antitumor activity and demonstrates a favorable safety profileTao Wang0Si-Qin Wang1Yin-Xiao Du2Dan-Dan Sun3Chang Liu4Shuang Liu5Ying-Ying Sun6Hai-Long Wang7Chun-Sheng Zhang8Hai-Long Liu9Lei Jin10Xiao-Ping Chen11Department of Clinical Pharmacology, Xiangya Hospital, Central South UniversityGeneScience Pharmaceuticals Co., LtdDepartment of Clinical Pharmacology, Xiangya Hospital, Central South UniversityGeneScience Pharmaceuticals Co., LtdGeneScience Pharmaceuticals Co., LtdGeneScience Pharmaceuticals Co., LtdGeneScience Pharmaceuticals Co., LtdGeneScience Pharmaceuticals Co., LtdGeneScience Pharmaceuticals Co., LtdGeneScience Pharmaceuticals Co., LtdGeneScience Pharmaceuticals Co., LtdDepartment of Clinical Pharmacology, Xiangya Hospital, Central South UniversityAbstract Background Targeting CD47/SIRPα axis has emerged as a promising strategy in cancer immunotherapy. Despite the encouraging clinical efficacy observed in hematologic malignancies through CD47-SIRPα blockade, there are safety concerns related to the binding of anti-CD47 antibodies to CD47 on the membrane of peripheral blood cells. Methods In order to enhance the selectivity and therapeutic efficacy of the antibody, we developed a humanized anti-CD47 monoclonal antibody called Gentulizumab (GenSci059). The binding capacity of GenSci059 to CD47 was evaluated using flow cytometry and surface plasmon resonance (SPR) methods, the inhibitory effect of GenSci059 on the CD47-SIRPα interaction was evaluated through competitive ELISA assays. The anti-tumor activity of GenSci059 was assessed using in vitro macrophage models and in vivo patient-derived xenograft (PDX) models. To evaluate the safety profile of GenSci059, binding assays were conducted using blood cells. Additionally, we investigated the underlying mechanisms contributing to the weaker binding of GenSci059 to erythrocytes. Finally, toxicity studies were performed in non-human primates to assess the potential risks associated with GenSci059. Results GenSci059 displayed strong binding to CD47 in both human and monkey, and effectively inhibited the CD47-SIRPα interaction. With doses ranging from 5 to 20 mg/kg, GenSci059 demonstrated potent inhibition of the growth of subcutaneous tumor with the inhibition rates ranged from 30.3% to complete regression. Combination of GenSci059 with 2.5 mg/kg Rituximab at a dose of 2.5 mg/kg showed enhanced tumor inhibition compared to monotherapy, exhibiting synergistic effects. GenSci059 exhibited minimal binding to hRBCs compared to Hu5F9-G4. The binding of GenSci059 to CD47 depended on the cyclization of N-terminal pyroglutamic acid and the spatial conformation of CD47, but was not affected by its glycosylation modifications. A maximum tolerated dose (MTD) of 450 mg/kg was observed for GenSci059, and no significant adverse effects were observed in repeated dosages up to 10 + 300 mg/kg, indicating a favorable safety profile. Conclusion GenSci059 selectively binds to CD47, effectively blocks the CD47/SIRPα axis signaling pathway and enhances the phagocytosis effects of macrophages toward tumor cells. This monoclonal antibody demonstrates potent antitumor activity and exhibits a favorable safety profile, positioning it as a promising and effective therapeutic option for cancer.https://doi.org/10.1186/s12967-023-04710-6Cancer immunotherapyCD47Pyroglutamic acidPhagocytosis |
| spellingShingle | Tao Wang Si-Qin Wang Yin-Xiao Du Dan-Dan Sun Chang Liu Shuang Liu Ying-Ying Sun Hai-Long Wang Chun-Sheng Zhang Hai-Long Liu Lei Jin Xiao-Ping Chen Gentulizumab, a novel anti-CD47 antibody with potent antitumor activity and demonstrates a favorable safety profile Journal of Translational Medicine Cancer immunotherapy CD47 Pyroglutamic acid Phagocytosis |
| title | Gentulizumab, a novel anti-CD47 antibody with potent antitumor activity and demonstrates a favorable safety profile |
| title_full | Gentulizumab, a novel anti-CD47 antibody with potent antitumor activity and demonstrates a favorable safety profile |
| title_fullStr | Gentulizumab, a novel anti-CD47 antibody with potent antitumor activity and demonstrates a favorable safety profile |
| title_full_unstemmed | Gentulizumab, a novel anti-CD47 antibody with potent antitumor activity and demonstrates a favorable safety profile |
| title_short | Gentulizumab, a novel anti-CD47 antibody with potent antitumor activity and demonstrates a favorable safety profile |
| title_sort | gentulizumab a novel anti cd47 antibody with potent antitumor activity and demonstrates a favorable safety profile |
| topic | Cancer immunotherapy CD47 Pyroglutamic acid Phagocytosis |
| url | https://doi.org/10.1186/s12967-023-04710-6 |
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